Mammalian ovaries contain a finite number of antral follicles. These follicles are essential for female reproduction because they contain the oocytes necessary for fertilization and they synthesize and secrete the hormones required for menstrual/estrous cyclicity, maintenance of the reproductive tract, and fertility. The organochlorine pesticide methoxychlor (MXC) poses a threat to female reproduction because it is commonly used in many countries and it selectively destroys antral follicles in a variety of species by increasing their rate of atresia (e.g., death of antral follicles). To date, little is known about the mechanisms by which MXC induces atresia of antral follicles. Preliminary data indicate that MXC induces atresia by altering the levels of highly conserved regulators of apoptosis known as the Bcl-2 family of proteins. In addition, preliminary data and the literature suggest that MXC and/or its metabolites may induce atresia by increasing the formation of reactive oxygen species and reducing the levels of proteins that protect cells from oxidative injury, including superoxide dismutase (SOD), glutathione (GSH), glutathione (GSH) peroxidase, GSH reductase, and catalase. Thus, based on preliminary data and the literature, the proposed work will to test the hypothesis that MXC and/or its metabolites cause atresia of antral follicles by altering the levels of selected Bcl-2 family members (Bcl-2 and Bax) and/or reactive oxygen species and proteins that protect cells from oxidative injury (i.e., SOD, GSH, GSH peroxidase, GSH reductase, and catalase). To test this hypothesis, the following specific aims will be completed: 1) determine whether MXC induces follicular atresia via a pathway involving selected Bcl-2 family members (Bcl-2 and Bax), 2) evaluate whether MXC induces follicular atresia by causing oxidative stress in antral follicles, and 3) determine whether MXC itself or the metabolites of MXC are responsible for follicular atresia. This work will greatly improve our understanding of the mechanisms by which MXC causes follicular atresia. In turn, this improved understanding may lead to the development of novel targets for the treatment and prevention of infertility that is caused by environmental chemicals.